This invention relates to novel antiproliferative and anti secrectory peptides that are inhibitory to vasoactive intestinal peptide receptor and are useful in the treatment of cancer. The invention particularly relates to the synthesis of lipid-peptide conjugates containing fatty acids of different sizes, which inhibits the binding of VIP to its receptors. The invention encompasses methods for generation of these peptides, composition containing these peptides and the pharmacological applications of these peptides especially in the treatment and prevention of cancer.
Vasoactive intestinal peptide (VIP) is a 28-amino acid neuropeptide, which was first isolated from the porcine intestine (Said, S. I. and Mutt, V., Science, 169, 1217-1218, 1970.) VIP acts as growth factor and plays dominant autocrine and paracrine role in the sustained proliferation of cancer cells. (Said, S. I., Peptides, 5, 143-150, 1984.) Gozes et al. have shown that VIP can serve as autocrine growth factor in lung tumors. (Gozes et al. Biomed. Res. 13 (suppl.2) 37, 1992).
The peptide sequence Leu-Met-Tyr-Pro-Thr-Tyr-Leu-Lys (SEQ ID NO: 1) is reported to be receptor binding inhibitor of vasoactive intestinal peptide (Said, and Mutt, Ann. N.Y. Acad. Sci., 1, 527, 1988). The role this octapeptide as VIP receptor binding inhibitor has been described in the U.S. Pat. No. 5,217,953. In our U.S. patent application Ser. No. 08/727,679 we have described the anti cancer role of this VIP binding receptor inhibitor in combination with other neuropeptide analogs. In another U.S. patent application Ser. No. 09/248,382 we have described the novel analogs of this VIP receptor binding inhibitor incorporating dialkylated amino acids. Keeping in view that lipophilization of bioactive peptides improves their stability, bioavailability and the ability to permeate biomembranes (Dasgupta, P. et al.; 1999, Pharmaceutical Res. 16, 1047-1053; Gozes, I. et al., 1996, Proc. Natl. Acad. Sci. USA, 93, 427-432.), in the present invention we have synthesized lipid conjugates of the peptide sequence Leu-Met-Tyr-Pro-Thr-Tyr-Leu-Lys (SEQ ID NO: 1) using fatty acids of different sizes, C2-C16 carbon atoms, at the N-terminal site of the peptide. Throughout the application the following abbreviation are used with the following meanings:
BOP: Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexofluorophospate
PyBOP: Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexofluorophospate
HBTU: O-Benzotriazole-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl-uronium-hexofluoro-phosphate
TBTU: 2-(1H-Benzotriazole-1yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate
Throughout the specification and claims, the amino acids residues are designated by their standard abbreviations. Amino acids denote L-configuration unless otherwise indicated by D or DL appearing before the symbol and separated from it by hyphen.
Throughout the specification and claims, the amino acids residues are designated by their standard abbreviations. Amino acids denote L-configuration unless otherwise indicated by D or DL appearing before the symbol and separated from it by hyphen.
The present invention relates to peptides of the following general formula
X-Leu-Met-Tyr-Pro-Thr-Tyr-Leu-Lys-Y 
wherein,
X is acetyl or straight, branched, or cyclic alkanoyl group of from 3-16 carbon atoms.
Y is a carboxy terminal residue selected from OH or amino; or a pharmaceutical acceptable salt of the peptides.